Ventolin HFA

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Ventolin HFA

CLINICAL PHARMACOLOGY

Mechanism of Action

In vitro studies and in vivopharmacologic studies have demons trated that albuterol
has a preferential effect on beta2-adrenergic receptors compared
with isoproterenol. While it is recognized that beta2-adrenergic
receptors are the predominant receptors in bronchial smooth muscle, data indicate
that there is a population of beta2-receptors in the human heart
existing in a concentration between 10% and 50% of cardiac beta-adrenergic receptors.
The precise function of these receptors has not been established [see WARNINGS
and PRECAUTIONS].

Activation of beta2-adrenergic receptors on airway smooth muscle
leads to the activation of adenylcyclase and to an increase in the intracellular
concentration of cyclic-3' ,5' -adenosine monophosphate (cyclic AMP). This increase
of cyclic AMP leads to the activation of protein kinase A, which inhibits the
phosphorylation of myosin and lowers intracellular ionic calcium concentrations,
resulting in relaxation. Albuterol relaxes the smooth muscles of all airways,
from the trachea to the terminal bronchioles. Albuterol acts as a functional
antagonist to relax the airway irrespective of the spasmogen involved, thus
protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations
are also associated with the inhibition of release of mediators from mast cells
in the airway.

Albuterol has been shown in most controlled clinical trials to have more effect
on the respiratory tract, in the form of bronchial smooth muscle relaxation,
than isoproterenol at comparable doses while producing fewer cardiovascular
effects. Controlled clinical studies and other clinical experience have shown
that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce
a significant cardiovascular effect in some patients, as measured by pulse rate,
blood pressure, symptoms, and/or electrocardiographic changes [see WARNINGS
and PRECAUTIONS].

Pharmacokinetics

The systemic levels of albuterol are low after inhalation of recommended doses.
A study conducted in 12 healthy male and female subjects using a higher dose
(1,080 mcg of albuterol base) showed that mean peak plasma concentrations of
approximately 3 ng/mL occurred after dosing when albuterol was delivered using
propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed
after administration of VENTOLIN HFA (albuterol sulfate inhalation aerosol) (Tmax = 0.42 hours) as compared to CFC-propelled
albuterol inhaler (Tmax = 0.17 hours). Apparent terminal plasma half-life of
albuterol is approximately 4.6 hours. No further pharmacokinetic studies for
VENTOLIN HFA (albuterol sulfate inhalation aerosol) were conducted in neonates, children, or elderly subjects.

Animal Toxicology and/or Pharmacology

Preclinical: Intravenous studies in rats with albuterol sulfate have
demonstrated that albuterol crosses the blood-brain barrier and reaches brain
concentrations amounting to approximately 5.0% of the plasma concentrations.
In structures outside the blood-brain barrier (pineal and pituitary glands),
albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated
the occurrence of cardiac arrhythmias and sudden death (with histologic evidence
of myocardial necrosis) when beta-agonists and methylxanthines are administered
concurrently. The clinical relevance of these findings is unknown.

Propellant HFA-134a is devoid of pharmacological activity except at very high
doses in animals (380 to 1,300 times the maximum human exposure based on comparisons
of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation.
These are similar to effects produced by the structurally related CFCs, which
have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was found to be rapidly absorbed
and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in
animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax)
and mean residence time are both extremely short, leading to a transient appearance
of HFA-134a in the blood with no evidence of accumulation.

Reproductive Toxicology Studies: A study in CD-1 mice given albuterol
sulfate subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses
at 0.25 mg/kg (less than the maximum recommended daily inhalation dose for adults
on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately
8 times the maximum recommended daily inhalation dose for adults on a mg/m²
basis). The drug did not induce cleft palate formation at a dose of 0.025 mg/kg
(less than the maximum recommended daily inhalation dose for adults on a mg/m²
basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females
treated subcutaneously with 2.5 mg/kg of isoproterenol (positive control).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of
19 fetuses (37%) when albuterol sulfate was administered orally at a 50 mg/kg
dose (approximately 680 times the maximum recommended daily inhalation dose
for adults on a mg/m² basis).

In an inhalation reproduction study in New Zealand white rabbits, albuterol
sulfate/HFA-134a formulation exhibited enlargement of the frontal portion of
the fetal fontanelles at and above inhalation doses of 0.0193 mg/kg (less than
the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A study in which pregnant rats were dosed with radiolabeled albuterol sulfate
demonstrated that drug-related material is transferred from the maternalcirculation
to the fetus.

Clinical Studies

Bronchospasm Associated With Asthma

Adult and Adolescent Patients 12 Years of Age and Older: The efficacy
of VENTOLIN HFA (albuterol sulfate inhalation aerosol) was evaluated in two 12-week, randomized, double-blind, placebo
controlled trials in patients 12 years of age and older with mild to moderate
asthma. These trials included a total of 610 patients (323 males, 287 females).
In each trial, patients received 2 inhalations of VENTOLIN HFA (albuterol sulfate inhalation aerosol) , CFC 11/12-propelled
albuterol, or HFA-134a placebo 4 times daily for 12 weeks' duration. Patients
taking the HFA-134a placebo inhaler also took VENTOLIN HFA (albuterol sulfate inhalation aerosol) for asthma symptom
relief on an as-needed basis. Some patients who participated in these clinical
trials were using concomitant inhaled steroidtherapy. Efficacy was assessed
by serial forced expiratory volume in 1 second (FEV1). In each of
these trials, 2 inhalations of VENTOLIN HFA (albuterol sulfate inhalation aerosol) produced significantly greater improvement
in FEV1 over the pretreatment value than placebo. Results from the
2 clinical trials are described below.

FEV1 as Percent Change From Predose in a Large,
12-Week Clinical Trial

Week 12

In the responder population ( ≥ 15% increase in FEV1 within 30
minutes postdose) treated with VENTOLIN HFA (albuterol sulfate inhalation aerosol) , the mean time to onset of a 15%
increase in FEV1 over the pretreatment value was 5.4 minutes, and
the mean time to peak effect was 56 minutes. The mean duration of effect as
measured by a 15% increase in FEV1 over the pretreatment value was
approximately 4 hours. In some patients, duration of effect was as long as 6
hours.

The second 12-week randomized, double-blind study was conducted to evaluate
the efficacy and safety of switching patients from CFC 11/12-propelled albuterol
to VENTOLIN HFA (albuterol sulfate inhalation aerosol) . During the 3-week run-in phase of the study, all patients received
CFC 11/12-propelled albuterol. During the double-blind treatment phase, VENTOLIN
HFA (91 patients) was compared to CFC 11/12-propelled albuterol (100 patients)
and an HFA-134a placebo inhaler (95 patients) in adolescent and adult patients
with mild to moderate asthma. Serial FEV1 measurements demonstrated
that 2 inhalations of VENTOLIN HFA (albuterol sulfate inhalation aerosol) produced significantly greater improvement
in pulmonary function than placebo. The switching from CFC 11/12-propelled albuterol
inhaler to VENTOLIN HFA (albuterol sulfate inhalation aerosol) did not reveal any clinically significant changes in
the efficacy profile.

In the 2 adult studies, the efficacy results from VENTOLIN HFA (albuterol sulfate inhalation aerosol) were significantly
greater than placebo and were clinically comparable to those achieved with CFC
11/12-propelled albuterol, although small numerical differences in mean FEV1
response and other measures were observed. Physicians should recognize that
individual responses to beta-adrenergic agonists administered via different
propellants may vary and that equivalent responses in individual patients should
not be assumed.

Pediatric Patients 4 Years of Age: The efficacy of VENTOLIN HFA (albuterol sulfate inhalation aerosol) was
evaluated in one 2-week, randomized, double-blind, placebo-controlled trial
in 135 pediatric patients 4 to 11 years of age with mild to moderate asthma.
In this trial, patients received VENTOLIN HFA (albuterol sulfate inhalation aerosol) , CFC 11/12-propelled albuterol,
or HFA-134a placebo. Serial pulmonary function measurements demonstrated that
2 inhalations of VENTOLIN HFA (albuterol sulfate inhalation aerosol) produced significantly greater improvement in
pulmonary function than placebo and that there were no significant differences
between the groups treated with VENTOLIN HFA (albuterol sulfate inhalation aerosol) and CFC 11/12-propelled albuterol.
In the responder population treated with VENTOLIN HFA (albuterol sulfate inhalation aerosol) , the mean time to onset
of a 15% increase in peak expiratory flow rate (PEFR) over the pretreatment
value was 7.8 minutes, and the mean time to peak effect was approximately 90
minutes. The mean duration of effect as measured by a 15% increase in PEFR over
the pretreatment value was greater than 3 hours. In some patients, duration
of effect was as long as 6 hours.